We have identified an evolutionarily conserved novel mutational mechanism that leads to FGF receptor (FGFR) over-accumulates on the cell surface. This phenomenon is observed in the Drosophila mutant and in the malignant renal cell carcinoma (RCC) culture. The likely cause is the mutation in the von Hippel-Lindau tumor suppressor gene (VHL). It was also noted that the over-accumulated FGFR leads to aberrant cell migration and induction of Etsl activity. Based on these and other preliminary data, a hypothesis is proposed that will study the novel intracellular mechanism that underlies the FGFR accumulation phenotype and how this aberrant signaling event, via Etsl, can modulate cell motility. We suspect that the pathway at least in part confers elevated cell motility by affecting integrin activities. We will utilize in vitro and in vivo model systems and employ cross-species comparative studies to dissect the signaling mechanisms. Aim 1 will dissect the vesicle transport pathway that results in FGFR over-accumulation and the effects of dysregulated signaling events. Aim 2 will analyze the role of Etsl in modulating the integrin activities, in relation to its potential target genes Skap55 and integrin |34. Aim 3 will examine the in vivo functional relationship between Etsl and integrins using Drosophila and Etsl knockout mouse primary cells as models. Finally, the important marker genes identified in this study will be verified in human tumor samples.